Show Summary Details
Page of

Suicide Risk in Bipolar Disorder: Comparing Lithium, Divalproex, and Carbamazepine 

Suicide Risk in Bipolar Disorder: Comparing Lithium, Divalproex, and Carbamazepine
Suicide Risk in Bipolar Disorder: Comparing Lithium, Divalproex, and Carbamazepine

Rachel Katz

, and Robert Beech

Page of

PRINTED FROM OXFORD MEDICINE ONLINE ( © Oxford University Press, 2016. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

Subscriber: null; date: 23 October 2019

Among patients treated for bipolar disorder, risk of suicide attempt and suicide death is lower during treatment with lithium than during treatment with divalproex.

Goodwin et al.1

Research Question:

Is there a difference in suicide risk for patients with bipolar disorder (BD) who are treated with lithium, divalproex, or carbamazepine?


Solvay Pharmaceuticals and Best Practice LLC

Year Study Began:


Year Study Published:


Study Location:

Two large integrated health plans in Washington and California (Group Health Cooperative and Kaiser Permanente, respectively)

Who Was Studied:

Patients 14 years or older with a diagnosis of BD with at least one filled prescription for lithium, divalproex or carbamazepine over a seven-year time period.

Who Was Excluded:

Patients with a previous diagnosis of schizophrenia, schizoaffective disorder prior to bipolar diagnosis, cognitive disorder, or dementia.

How Many Participants:


Study Overview:

See Figure 5.1 for a summary of the study design.

Figure 5.1 Summary of Study Design

Figure 5.1 Summary of Study Design

note: Only measured at one of the two sites.

Study Intervention:

This was a retrospective cohort study comparing outcomes among patients who were prescribed lithium, divalproex, or carbamazepine.


Mean of 2.9 years


Primary outcomes included suicide attempts (by hospital discharge diagnosis) and death by suicide (by death certificate). Secondary outcomes included suicidal behavior (by emergency department discharge diagnosis, not leading to hospitalization).


  • An analysis that adjusted for various confounds including year of BD diagnosis and use of other psychotropic medications found that those prescribed divalproex had a 2.7 (95% CI [1.1, 6.3], p = 0.03) times increased risk of death compared to those taking lithium.

  • Those taking carbamazepine did not have significant differences in rates of completed suicide compared with lithium (p = 0.61), though did have a 2.9 (95% CI [1.9, 4.4], p < 0.001) times higher risk of suicide attempts resulting in hospitalization.

  • There were 53 total completed suicides in the study (Table 5.1).

Table 5.1 Summary of Key Findings







Suicidal Behavior leading to ED visita,b






Suicide attempts resulting in hospitalizationb






Suicidal deathsb






a Kaiser Permanente site only.

bEvent rate per 1000 person-years.

Notes: Li = lithium. VPA = divalproex. CBZ = carbamazepine. ED = emergency department.

*P value vs lithium is statistically significant (<0.05).

Criticisms and Limitations:

Since this was not a randomized trial, confounding factors may have influenced the results. For example, patients with significant impulsivity, behavioral dysregulation or substance abuse may have preferentially have been prescribed divalproex or carbamazepine (given lithium’s narrow therapeutic index/overdose risk). Furthermore, psychiatrists may avoid prescribing lithium to patients with a history of suicide attempts or gestures, especially those with a history of medication overdose, due to its risk of overdose. This may have excluded the highest risk patients from the lithium cohort and skewed the results in favor of lithium.

Since this analysis was based on administrative data, it was not possible to assess the accuracy of bipolar diagnoses, the frequency or type of mood episodes (depression, mania or mixed) or the severity of suicidal behavior.

Additionally, there was no confirmation that study patients were actually took what they were prescribed.

Finally, accuracy of the number of suicide deaths was solely dependent on coroner diagnoses, which may underestimate the rate of suicide, especially in the context of drug overdose.2 Forensic psychiatric autopsy of all deaths (regardless of cause) in the cohort may have provided a more accurate estimate of completed suicide.

Other Relevant Studies and Information:

  • A previous small study suggested that those randomized to lithium had antisuicidal effects compared to those that received carbamazepine or amitriptyline.3

  • Another study found that lithium had an independent antisuicidal effect, independent from its mood stabilizing properties, in both unipolar and bipolar mood disorders.4

  • A large recent study further supports lithium’s antisuicidal and anti-self-injury effects are more powerful than other agents used for mood stabilization, including divalproex, carbamazepine, olanzapine, or quetiapine.5

  • Yet another study that randomized those with BD and previous suicide attempts to lithium or divalproex found no difference between groups, though the sample size was small and there were many confounders.6

  • American Psychiatric Association (APA) guidelines suggest there is “strong and consistent evidence” that long-term maintenance treatment with lithium, both for unipolar depression and BD, is associated with “major reductions in risk of both suicide and suicide attempts.”7

Summary and Implications:

This landmark study suggests that lithium therapy for BD is associated with a lower risk of suicide vs divalproex and carbamazepine. However, since this was not a randomized trial, confounding factors may have influenced the results, and thus the findings are not definitive. Nevertheless, based on this and other studies, the APA guidelines on treating suicidal behavior recommend considering lithium for suicidality prophylaxis preferentially to divalproex and carbamazepine among patients requiring mood stabilization.

Clinical Case: Choosing a First Mood Stabilizer

A 22-year-old woman presents to the hospital with her first manic episode. She has symptoms of euphoria, grandiosity, decreased need for sleep, and delusions about being the Queen of England. Her psychiatric history is notable for two previous depressive episodes and two previous suicide attempts. Based on the results of this study, which would be the best mood stabilizer for treatment of acute mania, mania prophylaxis and prevention of further suicidal behavior?

Suggested Answer

This study investigated the effect of lithium, divalproex, and carbamazepine on suicidality. Based on this and other studies, the APA recommended that psychiatrists consider the effect of lithium in reducing suicidal behavior in patients with BD. The APA also warns about the dangers of lithium overdose in these same recommendations.

The patient in the vignette has BD and is at increased risk for suicide especially considering her history of previous attempts. Based on the results of this study, lithium should be considered as a first-line mood stabilizer and would be indicated for treatment of acute mania and mania prophylaxis. Along with these indications, it would likely decrease the patient’s risk of future suicidal behavior and suicidal attempts more than divalproex or carbamazepine. The decision to start lithium over another mood stabilizer should be made carefully after weighing the risks and benefits in accordance with the patient’s preferences.


1. Goodwin, F. K., Fireman, B., Simon, G. E., Hunkeler, E.M., Lee, J., Revicki, D. (2003). Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA, 290(11), 1467–1473.Find this resource:

2. Hayes, J. F.Pitman, A., Marston, L., Walters, K., Geddes, J. R., King, M., & Osborn, D. P. (2016). Self-harm, unintentional injury, and suicide in bipolar disorder during maintenance mood stabilizer treatment: A UK population-based electronic health records study, JAMA Psychiatry, 73, 630–637.Find this resource:

3. Thies-Flechtner, K., Müller-Oerlinghausen, B., Seibert, W., Walther, A., & Greil, W. (1996). Effect of prophylactic treatment on suicide risk in patients with major affective disorders: Data from a randomized prospective trial. Pharmacopsychiatry, 29(3), 103–107.Find this resource:

4. Ahrens, B., & Müller-Oerlinghausen, B. (2001). Does lithium exert an independent antisuicidal effect? Pharmacopsychiatry, 34(4), 132–136.Find this resource:

5. Cipriani, A., Hawton, K., Stockton, & Geddes, J. R. (2013). Lithium in the prevention of suicide in mood disorders: Updated systematic review and meta-analysis. British Journal of Medicine, 346, f3646.Find this resource:

6. Oquendo, M. A., Galfalvy, H. C., Currier, D., Grunebaum, M. F., Sher, L., Sullivan, G. M., . . . Mann, J. J. (2011). Treatment of suicide attempters with bipolar disorder: A randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior. American Journal of Psychiatry, 168(10), 1050–1056.Find this resource:

7. Jacobs, D. G., Baldessarini, R. J., Conwell, Y., Fawcett, J. A., Horton, L., Meltzer, H., . . . Simon, R. I. (2010). Assessment and treatment of patients with suicidal behaviors. APA Practice Guideline. Washington, DC: American Psychiatric Association.Find this resource: